The long-range goal of this laboratory is to describe the sequence of events required for the persistence of synaptic change underlying information storage. Critical components of the sequence are proposed in the 'synaptic dialogue' hypothesis schematized in Figure 3 of this proposal and adapted from Routtenberg (1999). This hypothesis was formulated to provide a framework for incorporating the diverse set of molecular processes that regulate synaptic change as embodied in a model of information storage, long-term potentiation (LTP). We now wish to determine whether the hypothesis is applicable to information storage itself by testing it within behavioral situations where memory formation is required. The eight objectives may be briefly summarized as follows: (1) Define the learning and retention capability of mice in which the presynaptic protein kinase C (PKC) substrate is genetically altered; (2) Confirm that PKC activation by phorbol ester in wild type enhances retention and then determine the role of presynaptic PKC substrates; (3) Test the downstream influence of the N-methyl-D-aspartate (NMDA) receptor antagonists on pre synaptic PKC activation and retention, first in wild type mice and then the transgenics studied in objective 1; (4) Determine the generality to behavioral learning of the phorbol ester rescue effect seen in LTP studies in wild type mice; (5) Determine generality in transgenic mice; (6) In heterozygous (Hz) GAP-43 knockouts, in which levels of PKC substrate are reduced, will learning and memory change relative to wild type; (7) Evaluate the extent of phosphorylation of GAP-43 in each objective above using quantitative 2-dimensional gel electrophoresis; (8) Test the hypothesis that gene targeting manipulations can substitute for pharmacological manipulations (phorbol ester, 2-amino-5-phosphonovaleric acid (AVP)) in cyclic adenosine monophosphate (cAMP) responsive element (Cre)-locus of X-ingover (lox) P mutants. The present proposal provides fundamental information about the chemistry of memory and may lead to novel targets for therapeutics in memory disorders. Moreover, the malleability of the memory trace, its blockade and resurrection, suggests that a redefinition in cell biological terms of what constitutes its stability and fragility may be advanced by the present studies.